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Emilio Hirsch, PhD - "How human are mice? The tale of PIK3C2A and phosphatidylinositol (3,4)P2 in cytokinesis"

Professor of Experimental Biology Department of Molecular Biotechnology and Health Sciences Center for Molecular Biotechnology Via Nizza 52 10126 Torino – Italy
When Mar 05, 2020
from 12:00 PM to 01:15 PM
Where Tigem, Auditorium Vesuvius
Contact Name
Contact Phone 08119230659
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Abstract
Phosphoinositides (PI) have an active role in controlling the stability and remodeling of the cytoskeleton during cell division. In particular, impaired conversion of PI(4,5)P2 to PI(4)P resulting from inactivating mutations in OCRL PI 5-phosphatase causes abscission failure, which contributes to Lowe’s syndrome pathogenesis. Whether PI(4)P, generated by OCRL at the midbody, has a role in cell division, is still unknown. Here we demonstrated that fibroblasts from patients with homozygous loss-of-function mutations in PIK3C2A have impaired cytokinesis which leads to symptomatic features, including cataracts with secondary glaucoma and kidney defects, akin to oculocerebrorenal syndrome of Lowe (OCRL) patients. Mechanistically, PI3K-C2α, encoded by PIK3C2A, produced PI(3,4)P2 at the midbody plasma membrane by converting PI(4)P generated by OCRL phosphatase- and PI4KA kinase-activity. Local PI(3,4)P2 synthesis triggered the recruitment of  ESCRT-II to the midbody thus allowing proper cell division. Our work showed that the ESCRT-II subunit, VPS36, that binds PI(3)P in yeast, has acquired increased specificity for binding to PI(3,4)P2 during evolution, thus explaining a mammalian specific process controlling cytokinetic intercellular bridge cleavage. Our findings explains the molecular shift from yeast fission to an efficient midbody-driven cytokinesis in mice and humans.

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